Apolipoprotein (apo) E is a genetically polymorphic protein with three common isoforms in humans. We have identified a kindred with a mutant apoE, apoE-1Harrisburg, in which individuals heterozygous for this mutant allele have type III HLP. The mutation is a lysine to glutamic acid substitution at A.A. 146. This mutation results in a decreased fractional catabolic rate for apoE a presumably for apoB containing lipoprotein remnants resulting in type III HLP. The kinetics of metabolism of mutant forms of apoA-I have been investigated. Individuals with apoA-Milano (M) have low levels of apoA-I and HDL. ApoA-IM, which can form disulfide linked dimers, has a very complex metabolic pathway with rapid catabolism of monomeric apoA-IM that also results in rapid catabolism of normal apoA-I, and slow catabolism of apoA-IM dimers. This results in low plasma apoA-I and HDL levels with approximately equal amounts of apoA-IM and normal apoA-I in these heterozygotes. ApoA-IBaltimore (B) subjects have low HDL level with premature atherosclerosis. ApoA-IB is catabolized at a normal rate in a normal subject while both apoA-IB and normal apoA-I are catabolized at an increased rate in apoA-IB subjects. Therefore, the low HDL levels in the apoA-IB subjects are due either to a generalized upregulation of the apoA- I catabolic pathway by apoA-IB or to apoA-IB being a marker for a closely linked gene that upregulates the catabolism of apoA-I and HDL. Kinetic studies of apolipoprotein metabolism have been performed in three normal subjects utilizing nonradioactive heavy isotope labeled amino acids administered by bolus injection. There were no alterations in the metabolism of simultaneously administered radiolabeled apoA-I and apoB, and the catabolic rat, of nonradioactive heavy isotope labeled apoA-I, apoE, as well as VLDL, IDL, and LDL apoB were similar to results for radiolabeled studies of these apolipoproteins. This will be a useful new method to perform metabolic studies of apolipoproteins in humans.